Study on Molecular Pathophysiology of Schizophrenia

• Project/Area Number: 19390301
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Psychiatric science
• Research Institution: Chiba University
• Principal Investigator: HASHIMOTO Kenji Chiba University, 社会精神保健教育研究センター, 教授 (10189483)
• Co-Investigator(Kenkyū-buntansha): IYO Masaomi 千葉大学, 大学院・医学研究院, 教授 (50191903)
• Project Period (FY): 2007 – 2009
• Project Status: Completed (Fiscal Year 2009)
• Budget Amount: ¥14,300,000 (Direct Cost: ¥11,000,000、Indirect Cost: ¥3,300,000); Fiscal Year 2009: ¥3,510,000 (Direct Cost: ¥2,700,000、Indirect Cost: ¥810,000); Fiscal Year 2008: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2007: ¥6,370,000 (Direct Cost: ¥4,900,000、Indirect Cost: ¥1,470,000)
• Keywords: NMDA受容体 / 統合失調症 / グリシントランスポーター / D型セリン / D型アミノ酸 / D型アミノ酸酸化酵素 / 覚せい剤 / 薬物依存 / グリア細胞 / 動物モデル / 認知機能障害

Research Abstract

It is suggested that hypofunction of the NMDA receptors, a subtype of glutamate receptors, might be implicated in the pathophysiology of schizophrenia. In this study, we found that glycine transporter inhibitor or a combination of D-serine and D-amino acid oxidase inhibitor would be potential therapeutic drugs for schizophrenia.

Research Products

• [Journal Article] Neuropeptide S attenuates neuropathological, neurochemical and behavioral changes induced by the NMDA receptor antagonist MK-801 (2010)
  • Author(s): Okamura, N., Reinscheid, R., Ohgake, S., Iyo, M., Hashimoto, K.
  • Journal Title: Neuropharmacology 58 Pages: 166-172
  • Peer Reviewed
• [Journal Article] Comments to "The effect of risperidone on D-amino acid oxidase activity as a hypothesis for a novel mechanism of action in the treatment of schizophrenia" (2010)
  • Author(s): Hashimoto K
  • Journal Title: Journal of Psychopharmacology (In press)
  • Peer Reviewed
• [Journal Article] Glycine transport inhibitors for the treatment of schizophrenia. (2010)
  • Author(s): Hashimoto K
  • Journal Title: The Open Medicinal Chemistry Journal (In press)
  • Peer Reviewed
• [Journal Article] Effects of D-amino acid oxidase inhibitor on the extracellular D-alanine levels and the efficacy of D-alanine on dizocilpine-induced prepulse inhibition deficits in mice (2009)
  • Author(s): Horio, M., Fujita, Y., Ishima, T., Iyo, M., Ferraris, D., Tsukamoto, T., Hashimoto, K.
  • Journal Title: Open Clin.Chem.J. 2 Pages: 16-21
  • Peer Reviewed
• [Journal Article] Co-administration of D-amino acid oxidase inhibitor potentiates the efficacy of D-serine on prepulse inhibition deficits after administration of dizocilpine (2009)
  • Author(s): Hashimoto, K., Fujita, Y., Horio, M., Kunitachi, S., Iyo, M., Ferraris, D., Tsukamoto, T.
  • Journal Title: Biol.Psychiatry 65 Pages: 1103-1106
  • Peer Reviewed
• [Journal Article] Phencyclidine-induced cognitive deficits in mice are improved by subsequent subchronic administration of donepezil : role of sigma-1 receptors (2009)
  • Author(s): Kunitachi, S., Fujita, Y., Ishima, T., Kohno, M., Horio, M., Tanibuchi, Y., Shirayama, Y., Iyo, M., Hashimoto, K.
  • Journal Title: Brain Res. 1279 Pages: 189-196
  • Peer Reviewed
• [Journal Article] Co-administration of D-amino acid oxidase inhibitor potentiates the efficacy of D-serine on prepulse inhibition deficits after administration of dizocilpine. (2009)
  • Author(s): Hashimoto K, et al.
  • Journal Title: Biological Psychiatry 65 Pages: 1103-1106
  • Peer Reviewed
• [Journal Article] Co-administration of D-amino acid oxidase inhibitor potentiates the efficacy of D-serine on prepulse inhibition deficits after administration of dizocilpine. (2009)
  • Author(s): Hashimoto K et al.
  • Journal Title: Biological Psychiatry (in press)
  • Peer Reviewed
• [Journal Article] Phencyclidine-induced cognitive deficits in mice are improved by subsequent subchronic administration of the novel selective α7 nicotinic receptor agonist SSR180711 (2008)
  • Author(s): Hashimoto, K., Ishima, T., Fujita, Y., Matsuo, M., Kobashi, T., Takahagi, M., Tsukada, H., Iyo, M.
  • Journal Title: Biol.Psychiatry 63 Pages: 92-97
  • Peer Reviewed
• [Journal Article] D-serine and a glycine transporter inhibitor improve MK-801-induced cognitive deficits in a novel object recognition test in rats (2008)
  • Author(s): Karasawa, J., Hashimoto, K., Chaki, S.
  • Journal Title: Behav.Brain Res. 186 Pages: 78-83
  • Peer Reviewed
• [Journal Article] Modulation of D-serine levels in brains of mice lacking PICK1 (2008)
  • Author(s): Hikida, T., Mustafa, A. K., Maeda, K., Fujii, K., Barrow, R. K., Saleh, M., Oby, L., Huganir, R. L., Snyder, S. H., Hashimoto, K., Sawa, A.
  • Journal Title: Biol.Psychiatry 63 Pages: 997-1000
  • Peer Reviewed
• [Journal Article] Phencyclidine-induced cognitive deficits in mice are improved by subsequent subchronic administration of glycine transporter-1 inhibitor NFPS and D-serine (2008)
  • Author(s): Hashimoto, K., Fujita, Y., Ishima, T., Chaki, S., Iyo, M.
  • Journal Title: Eur.Neuropsychopharmacol. 18 Pages: 414-421
  • Peer Reviewed
• [Journal Article] Phencyclidine-induced cognitive deficits in mice are improved by subsequent subchronic administration of the antipsychotic drug perospirone : role of serotonin 5-HT_<1A> receptor (2008)
  • Author(s): Hagiwara, H., Fujita, Y., Ishima, T., Kunitachi, S., Shirayama, Y., Iyo, M., Hashimoto, K.
  • Journal Title: Eur.Neuropsychopharmacol. 18 Pages: 448-454
  • Peer Reviewed
• [Journal Article] Glycine and D-serine, but not D-cycloserine, attenuate prepulse inhibition deficits induced by NMDA receptor antagonist MK-801 (2008)
  • Author(s): Kanahara, N., Shimizu, E., Ohgake, S., Fujita, Y., Kohno, M., Hashimoto, T., Matsuzawa, D., Shirayama, Y., Hashimoto, K., Iyo, M.
  • Journal Title: Psychopharmacology 198 Pages: 363-374
  • Peer Reviewed
• [Journal Article] Food addictives and hyperactive behaviors in children (2008)
  • Author(s): Hashimoto, K.
  • Journal Title: Clin.Psychopharmacol.Neurosci. 6 Pages: 79-79
  • Peer Reviewed
• [Journal Article] NMDA-and β-amyloid_<1-42>-induced neurotoxicity is attenuated in serine racemase knockout mice (2008)
  • Author(s): Inoue, R., Hashimoto, K., Harai, T., Mori, H.
  • Journal Title: J.Neurosci. 28 Pages: 14486-14491
  • Peer Reviewed
• [Journal Article] Synthesis and biological evaluation of D-amino acid oxidase inhibitors. (2008)
  • Author(s): Ferraris D. et al.
  • Journal Title: Journal of Medicinal Chemistry 51(12) Pages: 3357-3359
  • Peer Reviewed
• [Journal Article] Phencyclidine-induced cognitive deficits in mice are improved by subsequent subchronic administration of glycine transporter-1 inhibitor NFPS and D-serine. (2008)
  • Author(s): Hashimoto K et al.
  • Journal Title: European Neuropsychopharmacology 18(6) Pages: 414-421
  • Peer Reviewed
• [Journal Article] D-serine and a glycine transporter inhibitor improve MK-801-induced cognitive deficits in a novel object recognition test in rats (2008)
  • Author(s): Karasawa J., et. al.
  • Journal Title: Bchavioral Brain Research 186 Pages: 95-97
  • Peer Reviewed
• [Journal Article] Phencyclidine-induced cognitive deficits in mice are improved by subsequent subchronic administration of glycine transporter-1 inhibitor NFPS and D-serine (2008)
  • Author(s): Hashimoto K., et. al.
  • Journal Title: European Neuropsychopharmacology
  • Peer Reviewed
• [Journal Article] Negative correlation between brain glutathione levels and negative symptoms in schizophrenia;a 3T H-MRS study (2008)
  • Author(s): Matsuzawa D., et. al.
  • Journal Title: PLos ONE 4(3)
  • Peer Reviewed
• [Journal Article] Glycine transporter-1 inhibitors as novel therapeutic drugs for schizophrenia (2007)
  • Author(s): Hashimoto, K.
  • Journal Title: CNS Agents Med.Chem. 7 Pages: 177-182
  • Peer Reviewed
• [Presentation] Reduction of D-serine in neonatal mouse brain caused schizophrenia-like behavioral abnormalities in adulthood ; a novel animal model of schizophrenia (2009)
  • Author(s): Hagiwara, H., Iyo, M., Hashimoto K.
  • Organizer: World Psychiatric Association-International Congress
  • Place of Presentation: Florence, Italy
• [Presentation] プレパルスインヒビションのQTL解析による責任遺伝子の同定 (2008)
  • Author(s): Watanabe, A., Toyota, T., Owada, Y., Hayashi, T., Iwayama, Y., Matsumata, M., Ishitsuka, Y., Maekawa, M., Ohnishi, T., Yamada, K., Hashimoto, K., Osumi, N., Yoshikawa, T.
  • Organizer: 第18回日本臨床精神神経薬理学会・第38回日本神経精神薬理学会合同学会
  • Place of Presentation: 東京都
  • Year and Date: 2008-10-02
• [Presentation] 脳内D-セリンの機能解析 (2008)
  • Author(s): 趙英らん, 宮一志, 橋本謙二, 森寿
  • Organizer: 第31回日本神経科学会大会
  • Place of Presentation: 東京都
  • Year and Date: 2008-07-10
• [Presentation] フェインサイクリジン投与による認知機能障害に及ぼす非定型抗精神病薬ペロスピロンの効果 (2008)
  • Author(s): 萩原裕子, 藤田有子, 石間環, 伊豫雅臣, 橋本謙二
  • Organizer: 第13回日本行動薬理研究会
  • Place of Presentation: 千葉市
  • Year and Date: 2008-06-06
• [Presentation] MK-801によるプレパルス抑制障害に対するNMDA受容体グリシンサイトアゴニストの改善作用 (2008)
  • Author(s): 金原信久, 清水栄司, 大掛真太郎, 藤田有子, 橋本謙二, 伊豫雅臣
  • Organizer: 第13回日本行動薬理研究会
  • Place of Presentation: 千葉市
  • Year and Date: 2008-06-06
• [Presentation] Phencyclidine-induced cognitive deficits are ameliorated by subsequent subchronic administration of donepezil : role of sigma-1 receptors (2008)
  • Author(s): Kunitachi, S., Fujita, Y., Ishima, T., Kohno, M., Hagiwara, H., Shirayama, Y., Iyo, M., Hashimoto, K.
  • Organizer: The 38th Annual Meeting of Society for Neuroscience
  • Place of Presentation: Washington DC, USA
• [Presentation] Co-administration of D-amino acid oxidase inhibitor potentiates the efficacy of D-serine on dizocilpine-induced cognitive deficits (2008)
  • Author(s): Fujita, Y., Ishima, T., Horio, M., Matsuzawa, D., Iyo, M., Ferraris, D., Tsukamoto, T., Hashimoto, K.
  • Organizer: The 38th Annual Meeting of Society for Neuroscience
  • Place of Presentation: Washington DC, USA
• [Presentation] [^<11>C]CHIBA-1001 as a novel PET ligand for α7 nicotinic receptors in the brain (2008)
  • Author(s): Hashimoto, K., Nishiyama, S., Ohba, H., Matsuo, M., Kobashi, T., Takahagi, M., Iyo, M., Kitashoji, T., Tsukada, H.
  • Organizer: The 38th Annual Meeting of Society for Neuroscience
  • Place of Presentation: Washington DC, USA
• [Presentation] フェインサイクリジン投与による認知機能障害に及ぼすグリシントランスポーター1阻害薬NFPSの効果 (2007)
  • Author(s): 藤田 有子, ら
  • Organizer: 第29回日本生物学的精神医学会・第37回日本神経精神薬理学会合同学会
  • Place of Presentation: 札幌市
  • Year and Date: 2007-07-12
• [Presentation] Synthesis of D-amino acid oxidase inhibitors and their effect on the plasma and brain levels of D-serine (2007)
  • Author(s): Duvall, B., Ferraris, D., Ko, Y. S., Thomas, A., Rojas, C., Tsukamoto, T., Hashimoto, K.
  • Organizer: 234^<th> ACS National Meeting & Exposition
  • Place of Presentation: Boston, MA, USA
• [Presentation] フェインサイクリジン投与による認知機能障害に及ぼす非定型抗精神病薬ペロスピロンの効果 (2007)
  • Author(s): 萩原裕子, 藤田有子, 石間環, 伊豫雅臣, 橋本謙二
  • Organizer: 第29回日本生物学的精神医学会・第37回日本神経精神薬理学会 合同年会
• [Presentation] フェインサイクリジン投与による認知機能障害に及ぼすα7ニコチン受容体アゴニストSSR 180711の効果 (2007)
  • Author(s): 石間環, 藤田有子, 松尾昌昭, 小橋達弘, 高萩誠, 塚田秀夫, 伊豫雅臣, 橋本謙二
  • Organizer: 第29回日本生物学的精神医学会・第37回日本神経精神薬理学会 合同年会
• [Presentation] フェインサイクリジン投与による認知機能障害に及ぼすグリシントランスポーター1阻害薬NFPSの効果 (2007)
  • Author(s): 藤田有子, 石間環, 茶木茂之, 伊豫雅臣, 橋本謙二
  • Organizer: 第29回日本生物学的精神医学会・第37回日本神経精神薬理学会 合同年会
• [Presentation] Glycine improves MK-801 induced prepulse inhibition deficits in a way similar to D-serine (2007)
  • Author(s): Kanahara, N., Shimizu, E., Ohgake, S., Hashimoto, K., Fujita, Y., Hashimoto, T., Shirayama, Y., Iyo, M.
  • Organizer: 第29回日本生物学的精神医学会・第37回日本神経精神薬理学会 合同年会
• [Presentation] セリンラセマーゼノックアウトを用いた脳内D-セリンの機能解析 (2007)
  • Author(s): 趙英らん, 高田義美, 橋本謙二, 崎村健司, 森寿
  • Organizer: 第30回日本神経科学大会・第50回日本神経化学大会・第17回日本神経回路学会大会 合同学会
• [Presentation] Phencyclidine-induced cognitive deficits are ameliorated by subsequent subchronic administration of the selective α7 nicotinic receptor agonist SSR180711 (2007)
  • Author(s): Hashimoto, K., Ishima, T., Fujita, Y., Matsuo, M., Kobashi, T., Takahagi, M., Tsukada, H., Iyo, M.
  • Organizer: The 37th Annual Meeting of Society for Neuroscience
  • Place of Presentation: San Diego, CA, USA
• [Presentation] Phencyclidine-induced cognitive deficits are ameliorated by subsequent subchronic administration of glycine transporter-1 inhibitor and D-serine (2006)
  • Author(s): Hashimoto, K., Fujita, Y., Ishima, T., Chaki, S., Iyo, M.
  • Organizer: The 36th Annual Meeting of Society for Neuroscience
  • Place of Presentation: Atlanta, GA, USA
• [Presentation] Genetic architecture that defines prepulse inhibition in mice and relevance of candidate genes to schizophrenia (2006)
  • Author(s): Watanabe, A., Toyota, T., Owada, Y., Hashimoto, K., Ishitsuka, Y., Ohba, H., Iwayama, Y., Itokawa, M., Nakata, A., Hayashi, T., Maekawa, M., Ohnishi, T., Yamada, K., Kondo, H., Osumi, N., Yoshikawa, T.
  • Organizer: The 36th Annual Meeting of Society for Neuroscience
  • Place of Presentation: Atlanta, GA, USA
• [Book] D-Serine and Schizophrenia.(In : Diamino Amino Acids, ed. Schafer HA, and Wohlbier LM) (2010)
  • Author(s): Hashimoto, K.
  • Publisher: Nova Publishers(in press)
• [Book] Glycine transporter inhibitors as therapeutic agents for schizophrenia(In : Frontiers in CNS Drug Discovery (Volume 1), ed. Choudhary, M. I. and Rahman A.) (2010)
  • Author(s): Hashimoto, K.
  • Publisher: Bentham Science Publishers(in press)
• [Book] Food coloring, sodium benzoate preservative and D-serine : Implication for behavior(In : The Handbook of Behavior, Diet and Nutrition, ed. Preedy, V. R.) (2010)
  • Author(s): Hashimoto, K.
  • Publisher: Springer Publishers(in press)
• [Book] The Handbook of Behavior, Diet and Nutrition (2010)
  • Author(s): Hashimoto K.
  • Publisher: Food coloring, sodium benzoate preservative and D-serine : implication for behavior(In press)
• [Remarks] ホームページ等
  • URL: http://www.m.chiba-u.ac.jp/class/shakai/index2f.htm